Immune cells which are activated by various stimuli have been shown to have augmented abilities to kill target cells. This project is studying various aspects of this phenomena, including the effect of age on the ability of such cells to be activated, alterations in the T cell antigen receptor with aging, and the impact of these changes on the ability to mount an effective immune response to xenogeneic stimuli. Another portion of the project is studying the mechanisms of killing, including the synergistic effects of IL-2 and IL-12, the role of oxidation reduction and the dissection of activation and apoptotic signaling pathways caused by cell activation. The biochemistry and cell biology of lymphocyte activation is also being studied in xenogeneic models. CBER regulates cellular therapies including activated lymphocytes. Understanding of this activation is conveyed to sponsors in the form of advice. This program investigates the optimization of cell activation, and the mechanisms involved, in autologous, allogeneic, and xenogeneic combinations. Xenotherapies are now a new biologic regulated by CBER, and we need to understand the reasons for the observed immunologic response to xenografts and xenotherapies. Sponsors have developed a variety of strategies utilizing drugs, biologics, and transgenic manipulations of the source animals as a means to influence the strength of the immunological response to xenografts and will continue to further refine these approaches.